In vitro Biotransfonnation of U-89843 and Its Deuterated Analog, U-141030

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Abstract

U-89843 is an important member of a lipid peroxidation family that are important
biologically. This drug was initially pursued by Pharmacia & Upjohn, Inc. for the
treatment of asthma. However, due to its observed genotoxicity, it is no longer considered
a drug candidate. Therefore, U-89843 and its deuterated analog, U-141030, were studied
in vitro in rat and human hepatic microsomes to determine characteristics of the
biotransformation of U-89843 so the mechanistic pathway that forms its reactive
intermediate can be determined. With this knowledge, it is hoped that new drug analogs
of U-89843 can be developed that are not genotoxic but still prove valuable for the
treatment of asthma. The measured isotope effect for the formation of U-97924 was
found to be 1.25 and 1.2 at 0.27 and 0.5 µM P450, respectively. These values are
indicative of a secondary isotope effect. A secondary isotope effect leads one to believe
that the mechanism responsible for the formation of U-97924 from U-89843 involves
electron abstraction followed by the addition of OH from water. Km and V max were
determined for U-89843 and U-141030 in untreated, pooled rat microsomes (Km = 4.09
µM and Vmax = 18.18 nmol/mg/min; Km= 3.36 µM and Vmax = 17.86 nmol/mg/min,
respectively) and human microsomes (Km = 21.87 µM and V max = 0.93 nmol/mg/min; Km= 8.80 µM and V max = 0.33 nmol/mg/min, respectively). The human P450 isoform
responsible for the biotransformation of U-89843 was found to be CYP3A4.